Multiple mechanisms maintain peripheral tolerance and prevent autoimmunity. These include deletion of self- reactive T cells in the thymus and checkpoints for appropriate lymphocyte activation in the periphery. There are also other regulatory elements that act to limit inflammation or which enforce homeostatic processes. These include the existence of Tregs, and a growing list of cytokines that control the balance between protective and pathological inflammatory responses. Many of these pathways are also associated with particular signaling molecules and the aberrant inflammation found in mice that lack STATS illustrate this principle. Relevant to this proposal, studies with Toxoplasma gondii have shown that although T cells are required to control this pathogen these cells also cause severe pathology. This provides an experimental system to study the factors that limit T cell activity and early reports identified IL-10 as essential to control immune hyper-reactivity during toxoplasmosis. Another example is IL-27, and IL-27R-/- mice infected with T. gondii develop a T cell mediated inflammatory response. Our studies revealed that IL-27 antagonizes the production of the T cell growth factor IL-2 and inhibits Thi, Th2 and Thi7 responses. More recently, IL-6 and IL-27 have been recognized as important inducers of T cell production of IL-10 and that these events are mediated through STATl and STAT3. Together these studies have provided new insights into some of the regulatory mechanisms that compliment the more established pathways that maintain peripheral tolerance. Nevertheless, the relative contribution of IL-6 and IL-27 to the levels of IL-10 produced during different stages of toxoplasmosis is uncertain. While'there is good evidence that there is a CD4+ (non-Treg) population that produces "protective" IL-10 our preliminary data suggest a model in which IL-6 and IL-27 regulate the production of IL-10 in distinct T cell subsets. However, IL-27 also has other properties and prevents Treg expansion and IL-27 transgenic mice develop an inflammatory condition characterized by systemic levels of cytokines and which may be related to a lack of Treg. Based on these data, three SA are proposed with the overarching aim to understand the distinct effects of IL-6 and IL-27, through their ability to activate various STATs, to limit T cell mediated inflammation and their role in Treg homeostasis. RELEVANCE (See instructions): T cells are critical components of the immune system which help the body to defend itself against infections. However, these responses can also lead to tissue damage. The studies proposed examine how cytokines prevent the development of pathological T cell responses during infection. These cytokines also promote suppressive T cell functions and how they influence these critical populations will be assessed.